Studies On Predictive And Prognostic Factors For Recurrent Or Metastatic Breast Cancer Treated With Small Molecular Anti-angiogenic Agents

Background:One of the key mediators of the tumor angiogenesis is the Vascular Endothelia Growth Factor (VEGF) and its signal pathway, which is the main target of anti-angiogenesis therapy recently. There has been some VEGF antagonists such as bevacizumab used in the breast cancer treatment. But the tyrosine kinase inhibitors(TKIs) that target the VEGF receptors are still in trial. It’s urgently needed to detect the predictive and prognostic factors for TKIs therapy.We evaluated safety and efficacy of apatinib, which targets VEGFR tyrosine kinases, in patients with chemotherapy refractory advanced breast cancer, and explore predictive and prognostic factors for TKIs, including clinical factors such as treatment-related adverse events, as well as circulating and histologic biomarkers. Method:All the patients came from phase II clinical trial of apatinib in advanced breast cancer. The patients had to be under the enrolled criteria, had measurable focus, and would got complete assessment of efficacy according to RECIST1.1criteria. Patients received oral apatinib500mg once daily in4-weeks cycle and adverse events were followed up. The primary end point was progress free survival(PFS), the secondary end point was objective response rate(ORR) and clinical benefit rate(CBR).Serum and plasma samples were collected on baseline and28d of the2nd cycle, Angiogenesis-related circulating cytokines were analyzed via xMAP(a multiplex assay) and ELISA. Immunohistochemistry for VEGFR2and phospho-VEGFR2(p-VEGFR2) were performed on pre-treatment formalin-fixed paraffin-embedded blocks or cut slides from tumor. The angiogenetic cytokines and clinical factors were profiled for apatinib efficacy by Kaplan-Meier, Log-rank test and Fisher’s exact test. COX and Logistic test were performed as multivariate regression analysis to define the independent prognostic factors.Result:From June2010to March2012, eighty patients were enrolled. Followed up to Mar1,2013, total PFS was3.77months, ORR was17.5%, CBR was37.5%。The most frequently observed drug-related adverse event were hypertension (55.0%,27grade1-2and17grade3-4), hand-foot syndrome (52.5%,29grade1-2and13grade3-4), and proteinuria (43.75%,29grade1-2and6grade3-4).According to univariate analysis, PFS of patients with hypertension(p=0.0096), HFSR(p=0.0025) and fatigue (p=0.0459)was longer, and their CBR was better(the p-value was<0.001,0.0025and0.005successively); PFS of patients age elder than 60y(p=0.0392), menopause (p=0.0358) and disease-free interval of≥15.5months (p=0.0176)was longer. But patients who had already received chemotherapy of2or more lines had shorter PFS(p=0.0221) and worse CBR(p=0.005). Also, patients with clinical benefit had longer PFS(p<0.0001). According to xMAP test, higher serum sVEGR2at baseline indicated longer PFS(p=0.0169). Afther performing immunohistochemistry on45paraffin-embedded blocks of all the enrolled patients. We found that patients with higher pVEGFR2tumor cell staining would get longer PFS(6.59m vs2.00m, p=0.0005) and better CBR(75%vs26.32%p=0.007).According to multivariate regression analysis, previous chemotherapy of2or more lines(p=0.033), treatment-related HFSR(p=0.005), higher pVEGFR2expression level(p=0.004) were the independent prognostic factors of PFS. HFSR(HR=0.500,95%CI0.308-0.809), higher pVEGFR2expression level of primary tumor (HR=0.354,95%CI0.174-0.719) were positive factors, while previous chemotherapy of2or more lines (HR=1.701,95%CI1.045-2.769) was negative factor. Treatment-related HFSR(p=0.046,HR=0.287,95%CI0.084-0.980), fatigue(p=0.041, HR=0.293,95%CI0.090-0.952)and higher pVEGFR2expression level of primary tumor(p=0.012, HR=0.0987,95%CI0.016-0.606) were independent prognostic factors of better CBR, while previous chemotherapy of2or more lines (p=0.049,HR=3.382,95%CI1.006-11.368) indicated worse one independently.Conclusion:Apatinib was tolerable and showed substantial antitumor activity in patients with advanced breast cancer. Among all the factors, previous chemotherapy of2or more lines, treatment-related HFSR, higher pVEGFR2expression level of primary tumor were three independent prognostic factors for PFS in apatinib-treated advanced breast cancer, with the first one being negative prognostic factor and the latter two being positive prognostic factors. Besides, HFSR, fatigue and PFS were correlated to better CBR significantly.